This project is designed to investigate the interactions of various cyclodiene insecticides with components of the liver microsomal mixed function oxidase system which metabolize insecticides, drugs and other foreign compounds. In acute, subacute, and chronic experiments, we will attempt to obtain quantitative estimates of the content and/or activity of the known components of this system, including cytochrome P-450, cytochrome c reductase, TPNH cytochrome c reductase and TPNH oxidase. The spectral interactions of selected cyclodienes with cytochrome P-450 will be examined and the binding constants Ksp and adsorption maximum Amax will be determined. Functional activity and kinetic constants of the MFO enzymes will be estimated by determining the rates of metabolism of heptachlor and aldrin and in some instances, other substrates such as hexobarbital and aniline. Attempts will be made to correlate specific changes in MFO parameters with overall enzyme activity. The metabolism of selected cyclodienes by rat intestinal microflora will be studied and the ability of these organisms from control and insecticide fed rats to form epoxides and polar metabolites will be examined. Additional experiments will be performed to determine which, if any, organisms have the ability to metabolize the cyclodiene compounds and if the activity is inducible. We also plan to study if the effects of perinatal exposure of rats to various insecticides will produce permanent changes with regard to the ability of the MFO to respond to enzyme inducers later in life. In these experiments rats will be exposed to test doses of heptachlor, aldrin, etc., either in utero or per os, during the first day of life. These animals will be given a challenging dose of the same compound at a later date.